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06-30-2017, 08:49 PM
Engineering Immune Orga**ids : An Interview with Prof. Ankur Singh from Cornell University
https://www.medgadget.com/wp-content/uploads/2017/06/lymphoma-up-close-300x201.jpgOrgan-on-a-chip tech**logies are redefining the way in which in vitro models help understand and recapitulate the in vivo environment. The immune system is particularly difficult to model in an in vitro environment because of the complexity of biological, mechanical, and chemical cues that modulate the immune cells. Prof. Ankur Singh, an assistant professor in the Sibley School of Mechanical and Aerospace Engineering at Cornell University, has led the development of organ-on-a-chip models to mimic the complex immune environment.
https://www.medgadget.com/wp-content/uploads/2017/06/Lymphoma-cells.jpgB cell lymphomas grow in orga**ids as clusters, similar to those in patients. The green fluorescent areas represent lymphoma cells, while the red represents support stromal cells.
The orga**id captures the early stages of a germinal center, which is the center for initiating an immu**logical response to infection. These orga**ids can be tailored to study specific diseases, like asthma, cancer, arthritis and transplant rejection. They represent a quick and easy approach to studying and understanding the mechanisms behind disease initiation and propagation.
A**ther model being developed in Prof. Singhâ??s lab is the Lymphoma-on-a-chip tech**logy, that accurately recapitulates the microenvironment for a tumor and can be used to study tumor progression. Moreover, these models can be used to study how the tumors respond to chemotherapy *****, providing new ways of studying tumor resistance.
Prof. Singh was recently awarded the Society for Biomaterials Young Investigator Award, and has several grants from the National Institute of Health to further develop his tech**logies. We recently had the opportunity to interview Prof. Singh to learn more about his team’s models.
Rukmani Sridharan, Medgadget: How representative are the immune orga**ids for studying immune disorders compared to current in vitro and in vivo models?
https://www.medgadget.com/wp-content/uploads/2017/06/prof-singh.jpgProf. Singh: The current version of the immune orga**id recapitulates selective aspects of the sub-anatomical parts of a lymph **de or spleen where immune cells, which have the potential to respond to infections by producing antibodies, are formed. These immune cells, called B cells, are present in our body as naأ¯ve, uneducated cells which receive signaling that transforms them into antibody secreting cells. The orga**id mimics the early stages of a germinal center, where B cell differentiation and initiation of immu**logical responses take place during infection. Maturing cells in current 2D systems are very short lived and lack the supporting tissue niche, on the other hand previous attempts to engineer 3D scaffolds have only shown formation of these highly specialized cells (called Germinal Center B cells) when implanted in vivo, exploiting the host microenvironment. Importantly, these studies did **t provide evidence of control over the rate of immune reaction ex vivo or in vivo, and ** studies have been reported that demonstrate differentiating B cells can survive ex vivo for successful conversion into the desired phe**type.
We submit that several aspects are still to be incorporated to make it completely similar to the in vivo environment; however, the system is suitable in its current form to determine how extracellular and intracellular factors can affect B cell activation. Understanding the factors that control the production, maturation and long-term survival of B cells is critical for more rapid development of disease-specific B cells, improved immu**therapeutic design (such as vaccines and immu**modulatory *****) and to provide mechanisms to target disorders resulting from defective B cell process (e.g. immu**deficiency with hyper-IgM, aging, as well as various B cell lymphomas or multiple myeloma).
Medgadget: How long can you keep these orga**ids in culture? Can they be constantly replenished /maintained to study the changes in immune response over time and changing environmental conditions?
Prof. Singh: The orga**ids are tunable and can be kept in culture for up to 14 days, however we already see 100-fold superior response over 4 days and have plentiful cells within 8-10 days. Although longer times are possible, we have **t tested this as the peak time for in vivo maturation is around 10 days. These are cultured in standard tissue culture plates and can be constantly replenished /maintained to study the changes in immune response over time and changing environmental conditions.
Medgadget: You have used gelatin and polyethylene glycol as base materials for building the orga**ids. How closely do these mimic the conditions **rmally found in the germinal centers in vivo? Do you anticipate using other materials in the future?
Prof. Singh: The rationale for using gelatin was the abundance of adhesive motifs that are found in the germinal center phase of the immune reaction. We have however developed a second generation designer immune orga**id which allows us to change the signalling ligand/protein as needed. This orga**id is composed of maleimide-functionalized PEG where a simple click chemistry is applied to â??clickâ?* short peptide of interest, and the peptide represents adhesive motifs found in larger bioadhesive proteins such as vitronectin, laminin, and fibronectin.آ* PEG itself is an inert material, so this allows us to precisely control the binding of cells to the material.
Medgadget: Your lymphoma-on-a-chip tech**logy sounds very interesting. Could you explain what your plans are with this model?
Prof. Singh: The Lymphoma-on-a-chip tech**logy recapitulates the microenvironment for a tumor and can be used to study tumor progression. Moreover, these models can be used to study how the tumors respond to chemotherapy *****, providing new ways of studying tumor resistance.
Medgadget: Organ-on-a-chip tech**logies are becoming more mainstream and more people are coming on board with the idea of using them. How far are we from replacing existing models with these tech**logies?
Prof. Singh: Organ-on-a-chip platforms are extremely useful for creating developmental and disease models as well as for conducting drug testing studies. They often recapitulate selective aspect of a target organ system and are very effective. Multiple labs are **w moving into whole body-on-chip models. Interestingly, almost all of these approaches lack immune system on chip, primarily because of the layers of complexity of this organ system. It would be less useful to simply put a single type of immune cells in conjunction with body or organ on chip, and I believe we, as engineers, need to think more deeply about multiple components of the immune system and how one immune cell orchestrates the performance of other immune cells. Our immune orga**ids are a good example of a system that entails much deeper immu**logy and focuses on a specialized area of the lymph **de. Our next steps would be to integrate other sub-anatomical parts of immune organs and make a more holistic organ on a chip.
Medgadget: What are your plans for commercialization of the tech**logy?
Prof. Singh: Our patents are pending and companies have expressed interest, but we are still in the early stages of assessing our best step forward.
https://www.medgadget.com/wp-content/uploads/2017/06/divider-3.jpg
Link:آ*Cornell’s Singh Researchآ*Group… (http://www.mae.cornell.edu/research/groups/icel/)
http://feeds.feedburner.com/~ff/Medgadget?d=yIl2AUoC8zA (http://feeds.feedburner.com/~ff/Medgadget?a=jamMMNpMzDs:em-ISQw_saQ:yIl2AUoC8zA) http://feeds.feedburner.com/~ff/Medgadget?d=qj6IDK7rITs (http://feeds.feedburner.com/~ff/Medgadget?a=jamMMNpMzDs:em-ISQw_saQ:qj6IDK7rITs) http://feeds.feedburner.com/~ff/Medgadget?i=jamMMNpMzDs:em-ISQw_saQ:gIN9vFwOqvQ (http://feeds.feedburner.com/~ff/Medgadget?a=jamMMNpMzDs:em-ISQw_saQ:gIN9vFwOqvQ)
http://feeds.feedburner.com/~r/Medgadget/~4/jamMMNpMzDs
https://www.medgadget.com/wp-content/uploads/2017/06/lymphoma-up-close-300x201.jpgOrgan-on-a-chip tech**logies are redefining the way in which in vitro models help understand and recapitulate the in vivo environment. The immune system is particularly difficult to model in an in vitro environment because of the complexity of biological, mechanical, and chemical cues that modulate the immune cells. Prof. Ankur Singh, an assistant professor in the Sibley School of Mechanical and Aerospace Engineering at Cornell University, has led the development of organ-on-a-chip models to mimic the complex immune environment.
https://www.medgadget.com/wp-content/uploads/2017/06/Lymphoma-cells.jpgB cell lymphomas grow in orga**ids as clusters, similar to those in patients. The green fluorescent areas represent lymphoma cells, while the red represents support stromal cells.
The orga**id captures the early stages of a germinal center, which is the center for initiating an immu**logical response to infection. These orga**ids can be tailored to study specific diseases, like asthma, cancer, arthritis and transplant rejection. They represent a quick and easy approach to studying and understanding the mechanisms behind disease initiation and propagation.
A**ther model being developed in Prof. Singhâ??s lab is the Lymphoma-on-a-chip tech**logy, that accurately recapitulates the microenvironment for a tumor and can be used to study tumor progression. Moreover, these models can be used to study how the tumors respond to chemotherapy *****, providing new ways of studying tumor resistance.
Prof. Singh was recently awarded the Society for Biomaterials Young Investigator Award, and has several grants from the National Institute of Health to further develop his tech**logies. We recently had the opportunity to interview Prof. Singh to learn more about his team’s models.
Rukmani Sridharan, Medgadget: How representative are the immune orga**ids for studying immune disorders compared to current in vitro and in vivo models?
https://www.medgadget.com/wp-content/uploads/2017/06/prof-singh.jpgProf. Singh: The current version of the immune orga**id recapitulates selective aspects of the sub-anatomical parts of a lymph **de or spleen where immune cells, which have the potential to respond to infections by producing antibodies, are formed. These immune cells, called B cells, are present in our body as naأ¯ve, uneducated cells which receive signaling that transforms them into antibody secreting cells. The orga**id mimics the early stages of a germinal center, where B cell differentiation and initiation of immu**logical responses take place during infection. Maturing cells in current 2D systems are very short lived and lack the supporting tissue niche, on the other hand previous attempts to engineer 3D scaffolds have only shown formation of these highly specialized cells (called Germinal Center B cells) when implanted in vivo, exploiting the host microenvironment. Importantly, these studies did **t provide evidence of control over the rate of immune reaction ex vivo or in vivo, and ** studies have been reported that demonstrate differentiating B cells can survive ex vivo for successful conversion into the desired phe**type.
We submit that several aspects are still to be incorporated to make it completely similar to the in vivo environment; however, the system is suitable in its current form to determine how extracellular and intracellular factors can affect B cell activation. Understanding the factors that control the production, maturation and long-term survival of B cells is critical for more rapid development of disease-specific B cells, improved immu**therapeutic design (such as vaccines and immu**modulatory *****) and to provide mechanisms to target disorders resulting from defective B cell process (e.g. immu**deficiency with hyper-IgM, aging, as well as various B cell lymphomas or multiple myeloma).
Medgadget: How long can you keep these orga**ids in culture? Can they be constantly replenished /maintained to study the changes in immune response over time and changing environmental conditions?
Prof. Singh: The orga**ids are tunable and can be kept in culture for up to 14 days, however we already see 100-fold superior response over 4 days and have plentiful cells within 8-10 days. Although longer times are possible, we have **t tested this as the peak time for in vivo maturation is around 10 days. These are cultured in standard tissue culture plates and can be constantly replenished /maintained to study the changes in immune response over time and changing environmental conditions.
Medgadget: You have used gelatin and polyethylene glycol as base materials for building the orga**ids. How closely do these mimic the conditions **rmally found in the germinal centers in vivo? Do you anticipate using other materials in the future?
Prof. Singh: The rationale for using gelatin was the abundance of adhesive motifs that are found in the germinal center phase of the immune reaction. We have however developed a second generation designer immune orga**id which allows us to change the signalling ligand/protein as needed. This orga**id is composed of maleimide-functionalized PEG where a simple click chemistry is applied to â??clickâ?* short peptide of interest, and the peptide represents adhesive motifs found in larger bioadhesive proteins such as vitronectin, laminin, and fibronectin.آ* PEG itself is an inert material, so this allows us to precisely control the binding of cells to the material.
Medgadget: Your lymphoma-on-a-chip tech**logy sounds very interesting. Could you explain what your plans are with this model?
Prof. Singh: The Lymphoma-on-a-chip tech**logy recapitulates the microenvironment for a tumor and can be used to study tumor progression. Moreover, these models can be used to study how the tumors respond to chemotherapy *****, providing new ways of studying tumor resistance.
Medgadget: Organ-on-a-chip tech**logies are becoming more mainstream and more people are coming on board with the idea of using them. How far are we from replacing existing models with these tech**logies?
Prof. Singh: Organ-on-a-chip platforms are extremely useful for creating developmental and disease models as well as for conducting drug testing studies. They often recapitulate selective aspect of a target organ system and are very effective. Multiple labs are **w moving into whole body-on-chip models. Interestingly, almost all of these approaches lack immune system on chip, primarily because of the layers of complexity of this organ system. It would be less useful to simply put a single type of immune cells in conjunction with body or organ on chip, and I believe we, as engineers, need to think more deeply about multiple components of the immune system and how one immune cell orchestrates the performance of other immune cells. Our immune orga**ids are a good example of a system that entails much deeper immu**logy and focuses on a specialized area of the lymph **de. Our next steps would be to integrate other sub-anatomical parts of immune organs and make a more holistic organ on a chip.
Medgadget: What are your plans for commercialization of the tech**logy?
Prof. Singh: Our patents are pending and companies have expressed interest, but we are still in the early stages of assessing our best step forward.
https://www.medgadget.com/wp-content/uploads/2017/06/divider-3.jpg
Link:آ*Cornell’s Singh Researchآ*Group… (http://www.mae.cornell.edu/research/groups/icel/)
http://feeds.feedburner.com/~ff/Medgadget?d=yIl2AUoC8zA (http://feeds.feedburner.com/~ff/Medgadget?a=jamMMNpMzDs:em-ISQw_saQ:yIl2AUoC8zA) http://feeds.feedburner.com/~ff/Medgadget?d=qj6IDK7rITs (http://feeds.feedburner.com/~ff/Medgadget?a=jamMMNpMzDs:em-ISQw_saQ:qj6IDK7rITs) http://feeds.feedburner.com/~ff/Medgadget?i=jamMMNpMzDs:em-ISQw_saQ:gIN9vFwOqvQ (http://feeds.feedburner.com/~ff/Medgadget?a=jamMMNpMzDs:em-ISQw_saQ:gIN9vFwOqvQ)
http://feeds.feedburner.com/~r/Medgadget/~4/jamMMNpMzDs